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Abstract

Prevention of cardiovascular disease has increasingly important health implications as our population ages. Menopause is associated with the development of cardiovascular risk factors and there are many plausible biological mechanisms through which estrogen may confer cardiovascular protection. Despite a wealth of observational data to support the use of estrogen, large randomized controlled trials failed to demonstrate a benefit. It is now becoming clearer that the beneficial cardiovascular effects of estrogen are greatest in younger women and those closest to menopause. This has led to the development of the timing hypothesis. Use of age-appropriate estrogen doses is crucial to maximize cardiovascular benefits while minimizing risk of adverse effects such as venous thromboembolism and stroke.

Keywords

coronary heart disease HRT observational studies randomized clinical trial stroke venous thromboembolism

Cardiovascular diseases (CVD), comprising coronary heart disease (CHD), stroke and venous thromboembolism (VTE), are the leading cause of mortality in women [201], responsible for almost a third of female deaths in the UK [202]. Marked gender differences exist in the incidence of CVD with women tending to develop CVD around 10 years later than men [1,2]. It has long been suspected that estrogen may confer protection against CVD, as the premenopausal hormonal milieu is associated with low cardiovascular risk and early studies demonstrated that the incidence of CVD increases sharply after the menopause [1]. Furthermore, menopause is associated with a number of adverse changes to classical cardiovascular risk factors, and women experiencing premature loss of ovarian function have an increased risk of ischemic heart disease [3,4] and possibly stroke [5]. However, the relationship between age, menopause and cardiovascular risk is complex, with recent studies showing no apparent acceleration of heart disease mortality at menopause [6].

The theory that HRT may be cardioprotective was well supported by observational studies and early randomized controlled trials (RCTs); however, great controversy arose following publication of the Women's Health Initiative (WHI) data [7]. Increases in CVD and breast cancer were reported along with recommendations that HRT should only be used at the lowest dose for the shortest possible duration [203], and due to the ensuing media frenzy, large numbers of women discontinued their HRT. These studies stimulated much discussion and debate, and now, almost a decade on, our understanding of the risks and benefits of HRT has much improved [8]. Despite initial reports of excess cardiovascular harm with HRT, subsequent analyses have shown that any increased risk is largely confined to older women or those furthest from menopause [9,10]. The differing effects of estrogen on cardiovascular risk, depending on age or time since menopause, has become known as the ‘timing hypothesis’.

In this article, we aim to provide an up-todate review of the most relevant literature on CVD and HRT, to enable the reader to understand how our knowledge has progressed in the wake of the WHI.

Biological mechanisms why estrogen may be beneficial

Many biological mechanisms have been identified as to why estrogen may be cardioprotective in postmenopausal women [11]. These can be divided into effects on classical risk factors for CHD, such as dyslipidemia and insulin resistance, or actions directly on the vessel wall and endothelial function.

Systemic effects

Dyslipidemia is a well-recognized cardiovascular risk factor and the menopausal transition is associated with adverse changes to women's lipid profiles, with increases in total and low-density lipoprotein (LDL) cholesterol and reductions in high-density lipoprotein (HDL) cholesterol [12]. Menopause is also associated with changes in other cardiovascular risk markers, including android fat deposition and deterioration of insulin sensitivity [13].

Oral estrogen therapy results in decreased LDL cholesterol and increased HDL cholesterol; however, this is at the expense of an increase in triglycerides [14]. Other beneficial effects include reductions in lipoprotein (a) [15], changes in LDL particle size and clearance, and inhibition of LDL oxidation [16]. Estrogen also has a positive effect on insulin metabolism and glucose [17], and a beneficial effect on body fat distribution [18].

Vascular effects

The short- and long-term effects of estrogen directly on the vascular wall are thought to play an even greater role than the metabolic effects. Estrogen has been shown in several animal models to prevent early atheroma [19,20] and this effect is mediated largely by effects on the endothelium via the ER-α [21]. Translational studies in nonhuman primates demonstrated that treatment of postmenopausal cynomolgus monkeys with 17β-estradiol was associated with a 50% reduction in atherosclerosis [22].

Animal models have demonstrated that estrogen has a beneficial effect on the vascular wall via a variety of different mechanisms, including improved vasodilation, accelerated endothelial healing and decreased proinflammatory mediators (Box 1). In healthy postmenopausal women, conjugated equine estrogens (CEEs) have been shown to improve endothelial function [23]. In addition, estrogen may have anti-ischemic action, as 17β-estradiol therapy has been associated with a reduction in coronary endothelial and myocardial ischemia-induced damage in mouse models [24].

Clinical data

Early observational studies

Three decades of observational studies appeared to consistently demonstrate the cardioprotective nature of postmenopausal HRT, with a reduction in cardiovascular deaths of approximately 40% reported [25,26].

Box 1.

Endothelial effects of estrogen.

Increased nitric oxide production [92]

Reduced endothelin-1 secretion [93]

Prevention of coronary spasm [94]

Accelerates re-endothelization [95]

Decreases endothelial permeability [96]

Prevents apoptosis [97]

Inhibition of platelet aggregation [98]

Increases prostacyclin levels via COX-2 [99]

Decreased cell adhesion molecules [100,101]

Decreased inflammatory factors (e.g., TNF-α, fibrinogen, VCAM-1, E-selectin, monocyte chemoattractant protein-1) [14,102,103]

The largest of these epidemiological studies was the Nurses' Health Study (NHS) [27], which examined the effects of HRT in 70,533 postmenopausal women with no known CVD. Women were classified as never users, past users or current users of HRT. After 20 years follow-up, current use of HRT, after adjustment for a variety of cardiovascular risk factors, was associated with a significantly decreased risk of a major coronary event (relative risk [RR]: 0.61; 95% CI: 0.52–0.71). However, higher estrogen doses and estrogen/progestogen therapy (rather than estrogen alone) were associated with a higher risk of stroke.

Randomized controlled trial data

Despite a wealth of observational evidence there have been few RCTs to support these findings. However, early RCTs using surrogate makers of atherosclerosis appeared to support the observational studies. Hodis and colleagues carried out a randomized, placebo-controlled trial involving 222 postmenopausal women with no known CVD [28]. They found that treatment with 1 mg of 17β-estradiol daily for 2 years was associated with reduced progression of subclinical atherosclerosis, as assessed using carotid artery intima-media thickness (IMT).

By contrast, results from the initial WHI publication appear to contradict previous data [7]. The WHI studies were a series of clinical trials and an observational study designed to assess the primary prevention of CVD, with hard clinical outcomes of CVD as end points. The trial had several different arms, including an estrogen plus progestin arm and an estrogen-only arm for hysterectomized women. The inclusion age for the studies was 50–79 years; however, they mainly involved older postmenopausal women, as the average age at enrolment was 63 years.

The estrogen/progestin arm examined the effects of oral CEE 0.625 mg and medroxyprogesterone acetate (MPA) 2.5 mg versus placebo in 16,608 postmenopausal women. This study halted early after 5.2 years due to an apparent increased risk of breast cancer in the treatment arm [7]. The initial analysis reported that estrogen/progestin therapy was associated with an increased risk of CHD events of almost 30% (hazard ratio [HR]: 1.29, nominal 95% CI: 1.02–1.63), with a particular increase in events in the first year following treatment. The estrogen only arm, involving 10,739 hysterectomized women receiving 0.625 mg CEE or placebo, was also terminated early, although not by the Data and Safety Monitoring Board, with an average follow-up of 6.8 years. The initial analysis from the estrogen-only arm also failed to show any cardiovascular benefit with estrogen use (HR: 0.91, adjusted 95% CI: 0.72–1.15) [29]. Results from the WHI observational study, which were similar to previously published observational data, have been reported along with the clinical trial data, and began to highlight reasons for the discrepancies between the results [30,31].

Despite initial conclusions from WHI that HRT does not offer protection against CVD, further data analysis and ongoing follow-up has brought these conclusions into question. Secondary analysis of both the CEE and CEE/MPA arms suggested that CHD was nonsignificantly reduced in younger women within 10 years of menopause using HRT and that increased risk was confined to those initiating therapy later after menopause [9]. Postintervention follow-up of patients from the estrogen-only arm for a mean of 10.7 years (with a mean duration of estrogen use of 5.9 years) echoed the initial findings, with no significant decrease in CHD across all ages (HR: 0.97, 95% CI: 0.75–1.25) [10]. However, analysis by age group showed a significant reduction of CHD in younger postmenopausal women (HR: 0.59, 95% CI: 0.38–0.90), with no significant increase or decrease in the 60–69 and 70–79 year old age groups. Furthermore, the lower incidence of breast cancer in the initial study became statistically significant with prolonged follow-up (HR: 0.77, 95% CI: 0.62–0.95).

In a subgroup of WHI participants, coronary artery calcification, a surrogate marker for atheromatous plaque burden, was measured by computerized tomography 1.3 years after study termination [32]. In this group of 1064 young hysterectomized women (age 50–59 years at study entry), the use of CEE compared with placebo was associated with a 20–40% reduction in calcified plaque, increasing to 50–60% in the treatment group with highest compliance.

How can the differences between the observational data & WHI be explained?

The surprising findings of the WHI RCTs led to much critique of the studies to try and address why they had generated findings so out of keeping with previous preclinical and epidemiological data.

One suggestion has been that the observational studies would have been subject to several forms of bias and, therefore, the results must have been inaccurate. Of particular relevance in HRT studies is the effect of ‘healthy user’ bias. Women who take estrogen are generally from a higher social class, better educated and have fewer risk factors for CVD than nonusers [33]. In addition, users of HRT are more likely to be subject to regular health checks and take further precautions to maintain their general well-being. However, in the NHS [27], bias did not appear to have a significant role as adjustment for confounding variables between users and nonusers did not affect the results, so this does not adequately explain the differing results with WHI. Another concern raised was that initial analyses of NHS data may have missed early cardiovascular events occurring in the 2 years following hormone initiation; however, further sensitivity analysis found that incomplete event capture did not account for the results of reduced CVD in HRT users [34].

Crucial differences in the study populations are likely to help explain many of the discordant findings. The observational studies generally involved women who started HRT around the time of the menopause for symptomatic relief. Subjects tended to continue treatment consistently and were followed-up for a long duration, often 10–15 years. By contrast, women in the WHI studies were started on HRT at an advanced age (average 63 years), often with a significant delay following menopause. Furthermore, subjects had elevated BMI, were not using HRT for symptom relief (only 12–17% had moderate-to-severe vasomotor symptoms [9]) and generally had much shorter duration of treatment and follow-up. The importance of age at initiation was highlighted in an ‘intention-to-treat’ comparison between WHI and NHS, which showed that HRs are in much greater agreement when only comparing women who commence HRT within 10 years of menopause [35].

The presence or absence of vasomotor symptoms in study populations is important as hot flushes are increasingly being recognized as a determinant of vascular health [36]. Hot flushes have been associated with risk factors for CVD, including increased cholesterol, elevated BMI and elevated blood pressure compared with nonflushers [37]. In addition, women with hot flushes have been shown to have adverse vascular changes such as impaired endothelial function [38,39], increased aortic calcification [38] and higher carotid artery IMT [40,41]. Conflicting data exist [42] and further evidence is needed to help fully understand the mechanisms by which vasomotor symptoms may influence cardiovascular risk.

Differing durations of follow-up between observational studies and RCTs may impact on findings. The progression of fatty streaks to clinically significant plaques can take up to 5 years and, therefore, if HRT prevents formation of new plaques, it may take several years for the benefit of HRT to become evident. This is supported by animal studies which observed that estrogen inhibits initiation but not progression of established lesions in mice [43].

Observational studies, which tend to have a much longer duration of follow-up, may therefore be better placed to detect benefit than RCTs with a shorter follow-up. This theory is supported by further analysis of the WHI estrogen-only arm, which demonstrated that lower cardiovascular event rates in women receiving estrogen compared with placebo only appeared to emerge from 7 years onwards (HR years 1–6: 1.08, 95% CI: 0.86–1.36; years 7–8: 0.46, 95% CI: 0.28–0.78) [44]. Similarly, data from the WHI estrogen plus progestogen arm showed that CVD benefit only appears in younger women after at least 6 years; although this trend did not reach statistical significance [45]. These findings suggesting that cardiovascular benefit from HRT requires prolonged exposure are more consistent with preclinical and observational studies with longer follow-up. Furthermore, this has more widespread implications for HRT use, given that many guidelines recommend that HRT should be used for the shortest possible duration, often interpreted as less than 5 years.

Timing hypothesis

These findings of differing effects of estrogen on younger, healthy, recently postmenopausal women compared with older women led to the development of the timing hypothesis, initially suggested almost a decade ago [46]. This hypothesis suggests that there is a window of opportunity where HRT may be beneficial for prevention of CVD in younger women, but that in older women, it does not appear to have the same benefits.

Biological plausibility exists to explain the timing hypothesis. Early in the atherosclerotic disease process the beneficial effects of estrogen predominate. However, diseased arteries with advanced atheroma appear to respond less well to estrogen and are, therefore, more vulnerable to the proinflammatory and thrombotic effects [47]. The anti-inflammatory effect of estrogen is somehow blocked by atheroma, either due to downregulation of estrogen receptors in the endothelium due to age or in the plaques themselves [48]. This can result in reduced vasodilatation, increased inflammation and plaque instability, potentially causing a prothrombotic effect in older women with underlying atherosclerosis.

Potential mechanisms through which estradiol may have a negative effect on plaque stability include increasing proinflammatory cyctokine release, stimulation of angiogenesis, inhibition of smooth muscle migration [49] and via the estrogenic effect on matrix metalloproteinases (MMPs). Increased expression of MMPs is associated with plaque rupture and hemorrhage, and MMPs are increased by estradiol, especially at higher doses [50]. Increased MMP levels would only likely cause a deleterious effect in arteries with advanced atheroma and, therefore, although MMP would also be increased in younger women, it would not cause harm.

Although these potentially adverse effects of estrogen have been identified, it has been suggested they are not harmful except when inappropriately high doses of estrogen are used [51], or in the presence of certain progestogens, particularly MPA, which acts to negate the beneficial effects of estrogen and may cause vasospasm [49].

The timing hypothesis has been demonstrated in nonhuman primate studies. In a series designed to investigate the effects of postmenopausal estrogen on nonhuman primates, cynomolgus monkeys were divided into three life stages [46]. Group 1 had little or no atherosclerosis prior to oophorectomy. Immediately after oophorectomy they commenced CEE for 30 months and were fed a moderately atherogenic diet. In this group, estrogen given at the time of oophorectomy was associated with a significant reduction in coronary artery atherosclerosis of 70% compared with placebo. Group 2 had moderate atherosclerosis prior to menopause, but again, early use of CEE was associated with 50–70% less atherosclerosis compared with controls. In group 3, however, monkeys with little or no atherosclerosis underwent oophorectomy and were treated with an atherogenic diet for 2 years prior to estrogen treatment. In this group with a delayed start to HRT (equivalent to 6 human years) no difference compared with placebo was observed in amount of atherosclerosis [46].

In humans, there is an absence of direct testing of the timing hypothesis because, although the WHI showed a trend towards cardioprotection in younger women, it was underpowered to detect a cardiovascular benefit in this age group [52]. However, ongoing postintervention follow-up observed a significant reduction of CHD (HR: 0.59,95% CI: 0.38–0.90) and total myocardial infarction (HR: 0.54, 95% CI: 0.34–0.86) in younger postmenopausal women [10].

These findings were in keeping with further analysis of the NHS data, which showed that the cardioprotective nature of estrogen was restricted to those starting HRT near the time of menopause (RR: 0.66, 95% CI: 0.54–0.8), whereas there was no significant reduction in CHD in women initiating therapy at least 10 years after menopause (RR: 0.87, 95% CI: 0.60–1.10) [34]. The timing hypothesis may also help explain why secondary prevention studies have failed to show any benefit from HRT [53].

Further clinical data in support of the timing hypothesis come from an influential randomized, placebo-controlled trial investigating the effect of 2–3 years treatment with HRT on cardiovascular mortality and severity of atherosclerosis in younger postmenopausal women [54]. The study involved 1458 postmenopausal women, with an average age of 55.8 years, who were followed for an average of 9.8 years. HRT (various combinations of estrogen plus progestin) was associated with a 46% reduction in mortality from CVD (HR: 0.54, 95% CI: 0.29-0.98) and significantly reduced aortic calcification.

Salpeter et al. performed a meta-analysis to examine the timing hypothesis in a larger population [55]. They examined 23 RCTs with a total of 39,049 subjects over 191,340 patient years. Subjects were classified into early postmenopause (<10 years postmenopause or <60 years of age) and late postmenopause. Results showed that HRT use was associated with significantly fewer CHD events (myocardial infarction or cardiac death) in the early postmenopausal group (odds ratio [OR] 0.68, 95% CI: 0.48–0.96), but not in older women (OR: 1.03, 95% CI: 0.91–1.16). In older women, HRT was associated with increased events in the year 1 (OR: 1.47, 95% CI: 1.12–1.92), but then reduced events after 2 years (OR: 0.79, 95% CI: 0.67–0.93).

The results of two randomized, placebo-controlled trials will hopefully provide further insight into the timing hypothesis, although both of these studies are examining surrogate markers rather than clinical events. The ELITE study is investigating the effect of oral 17β-estradiol plus vaginal progesterone in two different age groups – those less than 6 years postmenopausal and those more than 10 years [204]. The primary outcome is the rate of change of coronary artery IMT. Unfortunately, the dose of estrogen is the same in both groups, and hence the effect of a lower dose in older women will not be tested. The KEEPS study is investigating the effect of oral CEE or transdermal estradiol plus progesterone in women starting within 3 years of the menopause on carotid artery IMT and coronary artery calcium [56].

Stroke

CVD not only incorporates CHD, but also disorders of both the arterial and venous blood vessels. It is important, therefore, to also consider the impact of HRT on two important clinical outcomes: VTE and stroke.

The WHI estrogen alone arm terminated 8 months early after almost 7 years due to an apparent increased risk of stroke (HR: 1.39, estimated at an excess of 12 cases per 10,000 patient years) with 0.625 mg CEE [29]; although, surprisingly, this termination was not at the behest of the Data Safety and Monitoring Board. However, data remain conflicting regarding the exact risk of stroke with HRT. In the NHS, use of estrogen plus progestin (RR: 1.45, 95% CI: 1.10–1.92) and higher doses of CEE alone were associated with increased risk of ischemic stroke [27]. A recent meta-analysis found that oral HRT was associated with a 32% increased risk of stroke (OR: 1.32, 95% CI: 1.14–1.53) [57].

Risk of stroke appears to vary by dose and route of administration. A recent case–control study found that, consistent with previous results, there was approximately a 30% increased risk of stroke in users of oral HRT (RR: 1.28, 95% CI: 1.15–1.42) [58]. The authors estimated that this would amount to an attributable risk of 0.8 additional strokes per 1000 women per year. Overall, transdermal therapy was not associated with increased stroke risk (RR: 0.95, 95% CI: 0.75–1.20), but high-dose transdermal therapy alone (doses >50 μcg) was associated with increased risk (RR: 1.89, 95% CI: 1.15–3.11).

Unlike CHD, the timing hypothesis does not appear to apply to the risk of stroke, most likely because the risk of stroke is probably due to thrombotic rather than atherosclerotic mechanisms [59]. Therefore, although the literature is suggestive of an increased risk of stroke with oral HRT, there is a dose dependent relationship and the event rate is extremely low, especially in younger women.

Venous thromboembolism

It is well recognized that HRT is associated with increased risk of VTE; although, as with stroke, there is increasing evidence that the route of administration and estrogen dose can influence risk. Meta-analyses have shown that oral HRT is associated with increased risk of VTE (OR: 2.5, 95% CI: 1.9–3.4) [60]; however, there is no significant increase with transdermal therapy (OR: 1.2, 95% CI: 0.9–1.7). The risk with oral therapy is highest in the first year, declines thereafter and returns to that of never users on discontinuation.

Older studies failed to demonstrate a dose-dependent effect on VTE [61,62]; however, more recent data did find an association between oral estrogen dose and risk of VTE [63]. Of note, there was no association between estrogen dose and VTE risk when administered transdermally.

Data regarding thrombotic risk with estrogen alone compared with combination therapy remains contradictory, with one meta-analysis showing no significant difference between opposed and unopposed therapy [60], and another reporting a twofold increase in risk in those using combination therapy [57]. A recent prospective cohort study examined the risk of thrombosis in 80,308 postmenopausal women in which there were 549 fatal and nonfatal events. They found that oral, but not transdermal, therapy was associated with increased risk of VTE and also that the thrombotic risk differed depending on the progestogen used. There was no increased risk with micronized progesterone, pregnane or nortestosterone derivatives, but significantly increased risk with norpregnane derivatives (OR: 1.8, 95% CI: 1.2–2.7) [64]. Further data on the effects of progestogens are needed.

Different estrogens & route of administration

Other than estrogen dose and duration of treatment, several additional factors may influence the cardiovascular effects of HRT. In general, animal studies showing cardiovascular protection with estrogen have mainly used 17β-estradiol, in contrast to RCTs, which have predominantly used CEE. CEE and 17β-estradiol have different metabolic effects and, therefore, may exert different cardiovascular effects. CEE causes a greater rise in triglycerides than orally administered estradiol [65], and may have differing effects on insulin and glucose metabolism [11]. Several studies have compared oral CEE with transdermal estradiol on surrogate markers of CVD [66,67]; however, these are difficult to interpret as the dose and route of administration may influence results more than type of estrogen.

Few studies have directly compared the effects of different estrogens on clinical events, but a meta-analysis did not find any difference between the effects of CEE and estradiol on risk of coronary events, stroke or VTE [57]. The currently in progress KEEPS study is comparing the effect of CEE with estradiol on surrogate markers of CVD and should provide further information regarding the effect of these different estrogens [56]. However, the doses of estrogen in the oral and transdermal groups are not really equivalent, so the comparison between routes of administration will unfortunately not be strictly valid.

As discussed, route of HRT administration can affect the risk of thrombosis due to effects on the coagulation factors such as protein C, antithrombin and tissue factor pathway inhibitor. By avoiding first-pass hepatic metabolism, the transdermal route avoids these effects on coagulation pathways.

So does the route of administration affect CHD risk? Oral and transdermal therapy results in different metabolic effects. Oral therapy has been shown to reduce LDL and increase HDL more than transdermal, and while oral therapy tends to raise triglycerides, transdermal reduces them [65]. Although both oral and transdermal estradiol reduce fasting glucose and insulin, only oral therapy appears to benefit insulin sensitivity [17]. Furthermore, oral HRT has been shown in large, randomized trials to reduce the incidence of diabetes in postmenopausal women [68,69], whereas there are only data from a small observational study to show such an effect with transdermal estradiol [70].

It has been suggested that the pattern of early harm observed in the WHI RCTs may have been due to transient procoagulant effects and abnormal vascular modeling. By potentially avoiding procoagulant activity, transdermal therapy would be expected to have different effects on cardiovascular risk. Unfortunately, minimal data currently exist regarding the impact of route of therapy on CHD risk. A meta-analysis showed no difference in CHD events by route of estrogen, although only a small number of trials used transdermal therapy [57]. Available data would suggest that the dose of estrogen is probably more important than the route of administration on the risk of CHD, whereas both route and estrogen dose can influence stroke and VTE risk [71].

Role of progestogens

The progestogenic component of HRT appears to influence the cardiovascular effects, although existing data are conflicting. Comparison of the two arms of the WHI study suggests that the addition of MPA may account for the early deleterious outcomes seen in the CEE/MPA arm [7,29].

Several studies have shown that the cardioprotective effects of estrogen are attenuated following the addition of a progestogen. When examining coronary atheroma in monkeys, CEE alone was associated with a 72% reduction in atheroma; however, there was no difference between the untreated group and those receiving CEE plus MPA [72]. In humans, estradiol was associated with beneficial effects on endothelial function, as assessed by brachial artery flow-mediated vasodilation, but the effect was negated by the addition of MPA [23]. Data using hard clinical end points are limited, although meta-analyses have shown that addition of a progestogen doubled the risk of VTE but had no impact on risk of cerebrovascular disease or CHD [57].

Progestogens have distinct properties depending on their chemical derivatives and, therefore, different groups exert varying biological effects.

There are limited clinical data comparing the effect of different progestogens as most large RCTs have involved the use of MPA. The divergent metabolic effects of progestogens means these results cannot be expected to apply to other groups of progestogens. For example, HRT containing drosperinone has antihypertensive effects via the antimineralocorticoid properties of drosperinone [73]. Other studies have shown that MPA, but not progesterone, increases the risk of coronary vasospasm in hyperchoiestrolemic monkeys [74]. The androgenicity of progestogens influences their metabolic effects. Androgenic progestogens (e.g., norgestrel, levonorgestrel and MPA) reverse the HDL-raising effect of estrogen [75], decrease triglycerides and increase insulin resistance. By contrast, nonandrogenic progestogens, such as dydrogesterone, do not appear to counteract the beneficial effects of estradiol on insulin and lipids [76]. Further studies are needed to better understand the cardiovascular effects of the different progestogens.

Cardiovascular effects of other compounds with estrogenic properties

Tibolone

Tibolone is a synthetic molecule combining estrogenic, progestogenic and androgenic activity, often used for management of menopausal symptoms and prevention of postmenopausal osteoporosis. Tibolone has been shown to have favorable effects on lipid profile in postmenopausal women, resulting in reductions in total cholesterol, lipoprotein (a) and triglyceride: HDL ratio [77]. However, in contrast to estrogen therapy, tibolone is associated with reductions in HDL cholesterol [77,78], which may be detrimental to cardiovascular risk. Animal studies have demonstrated a beneficial effect of tibolone on atherosclerosis prevention [79,80]; however, studies of surrogate markers such as endothelial function in postmenopausal women have been contradictory [77,81]. The OPAL study was a clinical trial designed to study the cardiovascular effects of tibolone, in which 866 healthy postmenopausal women were randomized to tibolone 2.5 mg daily, CEE/MPA or placebo for 3 years [78]. This study found an increased progression of carotid artery IMT in both tibolone and CEE/MPA groups compared with placebo, raising concerns that tibolone may have adverse cardiovascular effects. The LIFT study was a randomized, placebo controlled study in 4506 older postmenopausal women (60–85 years) who received 1.25 mg tibolone daily [82]. Secondary outcomes in this study included cardiovascular events. The study was stopped prematurely after a median of 34 months treatment due to an increased risk of stroke in the tibolone group (RR: 2.19, 95% CI: 1.14–4.23), but no increase in coronary events or VTE was observed. Current evidence, therefore, suggests that tibolone may be associated with an increased risk of stroke in older postmenopausal women, but does not appear to adversely affect risk of CHD or VTE.

Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) are compounds that exert varying agonist and antagonist effects on estrogen receptors. Tamoxifen has been available for many years and its estrogen antagonist actions are used in the treatment of breast cancer, although vasomotor symptoms and endometrial hyperplasia can be problematic. Another agent in use is raloxifene, licensed for the prevention and treatment of postmenopausal osteoporosis, but can also adversely affect vasomotor symptoms. This class of drugs has been gaining much interest in recent years with attempts to maximize beneficial effects of estrogen agonism and antagonism while minimizing adverse effects.

Little is know about the long-term effects of the different SERMs on CVD. Data examining coronary events in women on tamoxifen have been conflicting [83,84], whereas animal studies have shown a benefit on atherosclerosis prevention, although to a lesser extent than that observed with CEE [85]. Raloxifene has been associated with reductions in total and LDL cholesterol [86], and stimulation of nitric oxide synthetase [87]. The RUTH study was a randomized placebo controlled trial investigating the use of raloxifene in 10,101 women [88]. Overall, they found no effect of raloxifene on coronary events, but there was a significantly increased risk of VTE and stroke. Further analysis of the RUTH data has highlighted the importance of age on cardiovascular outcomes, as the data showed a reduction in coronary events in women younger than 60 years initiating raloxifene treatment (HR: 0.59, 95% CI: 0.41–0.83) [89].

Of the newer third-generation SERMS, lasofoxifene at higher doses (0.5 mg) was associated with a significant reduction in major CHD events after 5 years of therapy (HR: 0.68, 95% CI: 0.5–0.93), but also with increased risk of VTE [90].

Another new generation SERM, bazedoxifene, has been combined with conjugated estrogen in an attempt to harness beneficial effects on bone and menopausal symptoms while avoiding adverse effects on breast and endometrial tissues. The 2-year safety data has shown no difference in the incidence of cardiovascular events compared with placebo, but event numbers were small and further long-term data are required [91].

Conclusion

CHD forms a significantly greater burden of disease than breast cancer or stroke, and the menopause is a pivotal time for reducing future cardiovascular risk. Many women will seek health advice at menopause and it should be seen as an important opportunity to implement disease prevention strategies through dietary and lifestyle changes along with pharmacological measures if necessary.

Executive summary

Background

With the aging population, the prevention of cardiovascular diseases has important public health implications.

Menopause is a major risk factor for the development of cardiovascular disease.

Biological mechanisms: why estrogen may be beneficial

Estrogen has widespread beneficial effects on the cardiovascular system, including improvements in lipid profile, glucose and insulin metabolism, and endothelial function.

Clinical data

Observational studies have consistently demonstrated the cardioprotective nature of postmenopausal HRT, whereas large randomized controlled trials (RCTs) have failed to show cardiovascular benefit from HRT and are suggestive of early harm.

How can the differences between the observational data & Women's Health Initiative be explained?

Many differences between study populations in observational studies and RCTs exist. RCTs were performed in older asymptomatic women with adverse cardiovascular risk factors, who commenced HRT with inappropriate doses and following a significant delay after menopause, in contrast to women in observational studies who generally started HRT around the time of the menopause for symptom relief.

Timing hypothesis

Current evidence suggests that there is a window of opportunity in which HRT appears to have beneficial effects on cardiovascular outcomes when initiated in women below 60 years of age or within 10 years of onset of the menopause.

In the presence of atheroma, HRT may cause cardiovascular harm through proinflammatory and thrombotic pathways; use of age-appropriate doses will help minimize risk.

Stroke & venous thromboembolism

HRT is associated with increases in risk of stroke and venous thromboembolism, although stroke remains a rare event in younger women. These risks appear to be dose dependent and may be minimized by using the transdermal route, which has little impact on coagulation.

Different estrogens & route of administration

Conjugated equine estrogens and estradiol exert different metabolic effects and, therefore, may vary in their effect on cardiovascular risk. Few studies have directly compared different estrogens by comparable routes and so further data are needed.

Transdermal therapy appears to have favorable effects on risk of venous thromboembolism and possible stroke. Current evidence suggests that route of administration does not significantly influence risk of coronary heart disease events.

Role of progestogens

Progestogens have distinct properties depending on their chemical derivatives and, therefore, may have varying cardiovascular effects. Further clinical data on the effect of different progestogens are needed.

Cardiovascular effects of other compounds with estrogenic properties

Tibolone may be associated with increased risk of stroke in older women but does not appear to adversely effect risk of venous thromboembolism or coronary heart disease.

Selective estrogen receptor modulators may have varying effects on the cardiovascular system. Development of new selective estrogen receptor modulators aims to maximize beneficial effects on the bone, brain and cardiovascular system without adverse effects on the breast and endometrium.

Cardiovascular risk is determined by a combination of genetic, lifestyle and environmental factors, but sex steroids can play an important role in modulating risk. There is a plausible metabolic basis for the cardioprotective effect of HRT, and this is supported by a wealth of preclinical and observational studies. Current evidence points to a window of opportunity, where greatest benefit in preventing atheroma progression is seen when HRT is initiated early after menopause. HRT may cause adverse cardiovascular effects through coagulation activation and abnormal vascular remodeling, although the use of age-appropriate doses and transdermal routes can help minimize these risks.

Future perspective

Over the next 5–10 years the public health implications of reducing cardiovascular risk in postmenopausal women will become increasingly important as rates of CHD continue to rise. We are unlikely to see large-scale randomized trials such as WHI in the near future, but smaller studies with surrogate markers will help further investigate the timing hypothesis and identify those who may receive greatest benefit from HRT. Ongoing research will also hopefully clarify the risks and benefits of low-dose and transdermal estrogens in older women or those with pre-existing CHD, and help gain greater insight regarding the optimum duration of estrogen therapy to impact on cardiovascular risk.

Further information is needed about the varying metabolic effects of different estrogens and progestogens, and whether this translates to clinical outcomes. In the future we will hopefully see the development of novel SERMs that have cardiovascular benefit but avoid adverse effects on breast tissue or the endometrium.

Footnotes

JC Stevenson has received research grants from Eli Lilly, Janssen-Cilag, Novo Nordisk, Organon/Schering-Plough, Schering, Shire, Solvay and Wyeth, and has served on Advisory Boards and/or received honoraria for lectures from Amgen, AstraZeneca, Bayer-Schering, Novo Nordisk, Orion, Proctor and Gamble, Servier, Solvay, Theramex and Pfizer/Wyeth. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Primary Prevention of Cardiovascular Disease with HRT

Abstract

Keywords

Biological mechanisms why estrogen may be beneficial

Systemic effects

Vascular effects

Clinical data

Early observational studies

Randomized controlled trial data

How can the differences between the observational data & WHI be explained?

Timing hypothesis

Stroke

Venous thromboembolism

Different estrogens & route of administration

Role of progestogens

Cardiovascular effects of other compounds with estrogenic properties

Tibolone

Selective estrogen receptor modulators

Conclusion

Future perspective

Footnotes

References